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E. Smit
Moderator of
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ORAL 28 - T Cell Therapy for Lung Cancer (ID 132)
- Event: WCLC 2015
- Type: Oral Session
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 6
- Moderators:P.S. Adusumilli, E. Smit
- Coordinates: 9/08/2015, 16:45 - 18:15, Four Seasons Ballroom F1+F2
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ORAL28.01 - Checkpoint Blockade Augments TCR Engineered Adoptive T Cell Therapy for Lung Cancer (ID 344)
16:45 - 18:15 | Author(s): E.K. Moon, R. Ranganathan, X. Liu, A. Lo, S. Kim, Y. Zhao, S. Albelda
- Abstract
Background:
Adoptive T-cell immunotherapy (ACT) has shown great promise in melanoma and hematologic malignancies; however one major limitation of engineered T cells targeting solid tumors is likely to be tumor microenvironment-induced hypofunction of the T cells. To study and limit this problem, we have developed a model in which human T cells engineered to target the antigen NYESO1 using a high-affinity engineered TCR (Ly95) are injected into mice bearing human A549 lung cancer cells. Using this model we demonstrate upregulation of PD1 and TIM3 on Ly95 TILs. We were able to augment T cell anti-tumor activity by combining Ly95 T cell therapy with anti-hPD1 and anti-hTIM3 antibodies.
Methods:
In vitro: Human T cells activated by anti-CD3/CD28 Dynabeads and transduced with lentivirus had 50% expression of Ly95 TCR as measured by flow cytometry. They were cocultured with marked tumor cells to measure IFNg release and antigen-specific killing. In vivo: Immunodeficient mice with 200mm[3] flank A549-A2-ESO (AAE) tumors received 10[7] T cells via tail vein. Three weeks later, tumors were harvested/digested, and human TILs were isolated/assesssed for tumor killing/IFNg secretion. This was repeated after the TILs were rested for 24hrs at 37[0]C/5%CO2. The number of TILs and PD1/TIM3 expression on the isolated TILs were assessed by flow cytometry at fresh harvest and post rest. The in vivo experiment was repeated comparing Ly95 T cells alone vs. Ly95 T cells plus either/both intraperitoneal (IP) anti-hPD1 or/and IP anti-hTIM3 at 10mg/kg every 5 days.
Results:
Ly95 TCR T cells were able to kill AAE tumor cells and secrete high amounts of IFNg in an antigen-specific/dose dependent fashion after 18hr coculture. 10[7 ]IV Ly95 T cells were able to slow AAE flank tumor growth as compared to control tumors (498mm[3 ]vs. 1009mm[3], p<0.05.) Flow cytometric analysis of harvested/digested tumors revealed that 5.2% of the tumor digest was human TILs. Freshly isolated TILs were hypofunctional in their ability to kill tumor cells and release IFNg when compared to cryopreserved Ly95 T cells (p<0.05.) After overnight rest away from tumor, TILs improved in function. Further analysis revealed that Ly95 TILs had upregulated their expression of PD1 and TIM3 (increase from 5 to 40% in PD1 and from 17 to 50% in TIM3.) Combining a single Ly95 T cell IV injection with multiple IP anti-hPD1 and anti-hTIM3 injections resulted in 43% reduction in flank tumor size compared to Ly95 T cell injection alone (189mm[3] vs. 332mm[3], p<0.05.)
Conclusion:
The PD1 and TIM3 pathways are involved in tumor-induced hypofunction of TCR engineered TILs. Combining anti-hPD1 and anti-hTIM3 antibodies with TCR T cells, and likely CAR T cells, will likely enhance the efficacy of these approaches in lung cancer and other solid tumors.
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ORAL28.02 - Mesothelin-Targeted CAR T-Cell Therapy for the Treatment of Heterogeneous Antigen-Expressing Lung Adenocarcinoma (ID 3172)
16:45 - 18:15 | Author(s): A. Morello, J. Villena-Vargas, M. Mayor, A.J. Bograd, D.R. Jones, M. Sadelain, P.S. Adusumilli
- Abstract
Background:
Adoptive T-cell therapy using chimeric antigen receptors (CAR) is an emerging strategy by redirecting T-cell effector functions against a cancer cell-surface antigen. To target lung adenocarcinoma (ADC) by CAR T-cell therapy, our laboratory has identified mesothelin (MSLN), a cell-surface antigen based on our published observation that MSLN is expressed in 60% of primary and metastatic lung ADC and is associated with tumor aggressiveness. Unlike hematological malignancies where CAR T-cell therapy has been successful targeting CD19, a cell-surface antigen that is uniformly expressed on B cells, MSLN expression intensity and distribution among lung ADC tumors is heterogeneous. The efficacy of CAR T-cell therapy in a heterogeneous antigen microenvironment is unknown. We hypothesized that the MSLN-targeted CAR T cells will be effective against high-antigen expressing lung ADC cells and the presence of even a small proportion of high MSLN expressing cells can enhance CAR T-cell cytotoxicity against low-antigen expressing lung ADC cells.
Methods:
Human peripheral blood T cells were retrovirally transduced with a 2[nd] generation of CAR targeting MSLN and bearing CD28 and CD3zeta activation domains. In vitro, we analyzed CAR T-cell cytotoxicity ([51]Cr release assay), effector cytokine secretion (Luminex assay), and proliferation (cell-counting assay) against lung ADC cell lines expressing variable levels of MSLN. In vivo, antitumor efficacy was evaluated by median survival and tumor bioluminescence (BLI) in mice bearing established homogeneous or heterogeneous lung ADC tumors.
Results:
In in vitro assays utilizing lung ADC cells with variable level of MSLN expression [low-antigen expression (EKVX or A549) or high-antigen expression (A549M and H1299M), control lung fibroblast (MRC5) or mesothelial cells (MET5A)], CAR T cells exhibit antigen-specific cytolytic activity, effector cytokine secretion and proliferation in proportion to the MSLN expression on cancer cells. In vivo, a single low dose of CAR T cells eradicates primary and metastatic established tumor expressing high-level of MSLN and prolongs tumor free survival (41 days vs not reached, p<0.0001). We next evaluated CAR T-cell efficacy in heterogeneous antigen microenvironment by mixing low and high antigen-expressing cells (A549 expressing firefly luciferase/A549M) and assessed the A549 tumor burden only by bioluminescence imaging. In the presence of A549M cells, CAR T cells are able to prolong progression-free survival of A549 tumor burden (22 days vs 0 days in absence of A549M cells). Further mechanistic studies demonstrated that CAR T cells lysed an additional 5%-15% A549 or EKVX cells in the presence of H1299M or A549M cells (p<0.05) without off-target cytotoxicity. Antigen-activated CAR T cells were effective against low-antigen expressing lung ADC cells without the need for high-antigen expressing cells in the coculture.
Conclusion:
Our results provide scientific rationale to translate MSLN-targeted CAR T-cell therapy for the treatment of the primary and metastatic lung ADC. A phase I clinical trial (NCT02414269) that includes lung ADC patients is initiated at our center.
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ORAL28.03 - Genetic-Engineering Strategies to Enhance CAR T-Cell Therapy Efficacy against PD-L1 Expressing Lung Adenocarcinoma and Mesothelioma (ID 3139)
16:45 - 18:15 | Author(s): L. Cherkassky, A. Morello, J. Villena-Vargas, M. Mayor, D.R. Jones, M. Sadelain, P.S. Adusumilli
- Abstract
Background:
This abstract is under embargo until September 8, 2015 and will be distributed onsite on September 8 in a Late Breaking Abstract Supplement.
Methods:
Results:
Conclusion:
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ORAL28.04 - Tumor-Targeted Radiation Therapy Helps Overcome the Solid Tumor T-Cell Infiltration Barrier and Promotes Mesothelin CAR T-Cell Therapy (ID 3142)
16:45 - 18:15 | Author(s): M. Mayor, J. Villena-Vargas, A. De Biasi, A. Morello, D.R. Jones, M. Sadelain, P.S. Adusumilli
- Abstract
Background:
Translating recent chimeric antigen receptor (CAR) T-cell therapy successes in hematologic malignancies to solid cancers requires overcoming barriers unique to solid tumors such as inadequate tumor infiltration, proliferation, and persistence. Our laboratory has published the rationale to target mesothelin (MSLN), a cell-surface antigen expressed in the majority of thoracic malignancies. We hypothesized that the immune modulating effects of low-dose radiation therapy (RT) would enhance the infiltration and proliferation of mesothelin-targeted CAR T-cell therapy for thoracic cancers, thereby achieving long-term tumor eradication.
Methods:
Using human T cells retrovirally transduced to express mesothelin-targeted CARs, we evaluated T-cell cytotoxicity by chromium release assay, proliferation by cell count assay, cytokine-release by multiplex ELISA, phenotype by flow cytometry, and chemokine receptor profiles by PCR against MSLN-expressing mesothelioma and lung cancer cell lines with and without localized RT. In clinically relevant mouse models (NOD/SCID gamma mice) with established MSLN-expressing tumors, we monitored therapy response, T-cell kinetics and anti-tumor efficacy by utilizing bioluminescent imaging (BLI), and conducted flow cytometric analysis of splenic/peripheral blood T cells for characterization of CAR T-cell effector phenotype.
Results:
RT did not enhance CAR T-cell cytotoxicity. In vitro, RT enhanced CAR T-cell migration in chemotactic assays, and correlatively induced the secretion of chemokines by tumor cells (Fig.1A). In vivo, RT resulted in dose dependent chemokine secretion with robust early intratumoral CAR T-cell accumulation (p<0.05, Fig.1B) as demonstrated by T-cell BLI. Ex vivo tumor analysis by flow cytometry on day 7 post T-cell administration confirmed that RT increased early infiltration and proliferation (p<0.05). Also, single low-dose RT potentiated the efficacy of systemically administered CAR T cells (median survival 30d vs. 79d, p= 0.02) with at least 50% tumor eradication up to 100 days even with a 30-fold decreased dose (Fig.1C&D). Furthermore, in mice with tumor eradication, harvested spleen T-cell analysis at day 56 demonstrated a greater number of persisting CAR T cells in mice treated with RT (p=0.02, Fig.1E).Figure 1
Conclusion:
Our data provides the rationale to use localized RT as a preconditioning regimen prior to CAR T-cell administration in a clinical trial for thoracic malignancies. Furthermore, our mechanistic observation of RT-induced, chemokine-mediated, enhanced T-cell infiltration may also assist the trafficking of endogenous anti-tumor T cells, thereby shifting the balance towards a cohesive anti-tumor immune microenvironment.
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ORAL28.05 - Mesothelin and MUC16 (CA125) Are Antigen-Targets for CAR T-Cell Therapy in Primary and Metastatic Lung Adenocarcinoma (ID 3159)
16:45 - 18:15 | Author(s): T. Eguchi, H. Ujiie, A. Morello, K. Kadota, D.H. Buitrago, K. Woo, D.R. Jones, W.D. Travis, M. Sadelain, P.S. Adusumilli
- Abstract
Background:
Chimeric antigen receptor (CAR) T-cell therapy has shown durable remissions in hematological malignancies targeting cancer-antigen CD19. Ideal cancer-antigen targets for CAR T-cell therapy are antigens overexpressed on cancer cell-surface with limited expression in normal tissues, associated with tumor aggressiveness and expressed in a large cohort of patients. In our search for such candidate antigens in lung adenocarcinoma (ADC), we investigated the overexpression of Mesothelin (MSLN), MUC16 (CA125), and the combination of MSLN-MUC16 as the interaction of both antigens has been shown to play a role in tumor metastasis.
Methods:
In patients with stage I lung ADC (n = 912, 1995 - 2009), a tissue microarray consisting of 4 cores from each tumor and normal lung tissue was used to examine the antigen-expression characteristics, and their association with cumulative incidence of recurrence (CIR). Autologous metastatic tumor tissue was available from 36 patients. Differences in CIR between groups were tested using the Gray method (for univariate nonparametric analyses) and Fine and Gray model (for multivariate analyses).
Results:
MSLN and MUC16 were not expressed in normal lung tissue. In primary and metastatic lung ADC tumors, MSLN was expressed in 69% and 64%, MUC16 was expressed in 46% and 69%, both antigens were present in 50% and 33%, and either antigen were present in 33% and 49% respectively. On univariate analysis, patients with high MSLN expression had high risk of recurrence than low expression [5-year CIR, High: 25.1% vs Low: 17.6%, P = 0.017]. Patients with high MUC16 expression had high risk of recurrence than low expression [5-year CIR, High: 24.2% vs Low: 14.0%, P < 0.001]. Patients with high MUC16 and high MSLN had higher risk of recurrence than low expression [5-year CIR, High risk (High MUC16 and High MSLN): 27.6%, Intermediate risk (High MUC16 and Low MSLN): 24.2%, Low risk (Low MUC16): 13.6%, P < 0.001]. On multivariate analysis, increased MUC16-MSLN expression was associated with recurrence [Hazard ratio, 2.57 95% Confidence interval 1.41 – 4.68 P = 0.002], even after adjustment for currently known markers of lung ADC aggressiveness (gender, surgical procedure, stage, architectural grade and lymphatic invasion). High expression of MUC16 in the primary tumor was associated with high expression at recurrence sites.
Conclusion:
MSLN, MUC16 or a combination of expression of both antigens in patients with primary lung ADC is associated with increased risk of recurrence, a retained overexpression at metastatic sites in advanced lung ADC indicating that MUC16-MSLN expression is a marker of tumor aggressiveness. Expression in the majority of lung ADC patients imparting aggressiveness with no expression in normal lung provides the rationale to target MSLN and MUC16 for lung ADC CAR T-cell therapy.
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ORAL28.06 - Discussant for ORAL28.01, ORAL28.02, ORAL28.03, ORAL28.04, ORAL28.05 (ID 3463)
16:45 - 18:15 | Author(s): E. Smit
- Abstract
- Presentation
Abstract not provided
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Author of
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MINI 18 - Radiation Topics in Localized NSCLC (ID 139)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Treatment of Localized Disease - NSCLC
- Presentations: 1
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MINI18.03 - Immune Activation in Early Stage Non-Small Cell Lung Cancer (NSCLC) following Stereotactic Ablative Radiotherapy (SABR) and Surgery (ID 2123)
16:45 - 18:15 | Author(s): E. Smit
- Abstract
- Presentation
Background:
An anatomical surgical resection is considered to be the standard of care in fit patients, but non-randomized comparative effectives studies suggest that survival outcomes may be similar following SABR. An antitumor immune microenvironment was found to be a prognostic factor in surgically resected early stage NSCLC. SABR has been reported to activate the immunesystem in malignant diseases via a number of mechanisms. We investigated the impact of both surgery and SABR in early stage NSCLC on the immunesystem, studied in peripheral blood over time.
Methods:
This is a non-randomised trial. Treatment by either surgery or SABR treatment for early stage (cT1-T2aN0M0) were determined by an institutional multi-disciplinary tumorboard, and in accordance with the patient’s preference . SABR was typically delivered in 3-8 fractions in 1-2 weeks, based on risk-adapted radiotherapy schemes that delivered a biologically effective dose of >100 Gy. Surgery generally involved a VATS lobectomy. Blood was collected prior to treatment, and at weeks 1, 2, 3 and 6 after start of treatment. The peripheral blood mononuclear cell (PBMC) fraction was isolated and was stimulated for 4 hours with phorbol 12-myristate 13-acetate (PMA) and ionomycin, to activate the T cells. Subsequently, the T-cells cells were harvested and analyzed by flow cytometry on the expression of CD4 and/or CD8, granzyme B and interferon (IFN) γ. As PD-1 expression is induced in T-cells after antigen exposure the expression of PD-1 was determined. Changes of population proportions between the different time points were analyzed with the related-samples Wilcoxon signed rank test.
Results:
23 early stage non-small cell lung cancer (NSCLC) patients were included in the study. Of these, 13 patients underwent surgical resection at a mean age (±standard deviation) of 62,9± 8,4 years, and 10 patients who underwent SABR at a median age of 70,0 ±10,4 years. SABR patients had more comorbidities, and a poorer WHO performance score, but clinical tumor stage was comparable. A significant increase in the proportion of IFNγ[+]Granzyme B[+] CD8 T cells (p<.05) was observed at week 2 in the SABR treated group, whereas no difference was found after surgical resection. The PD1[+] fraction of CD4[+] T cells was significantly increased at week 2 in the SABR treated group (p<.05), whereas no differences were seen at two weeks after surgical resection. Proportions of PD1[+ ]CD4 T cells remained elevated in the SABR group at week 3 and 6. A similar trend was observed in the CD8[+] T cell population, although this did not reach statistical significance (p<.1).
Conclusion:
SABR but not surgery, enhances T-cell activation and PD-1 upregulation. The results of our study warrant further investigation as to whether SABR induces an anti-tumor response in patients with early stage NSCLC . The upregulation of PD-1 inherently accompanied with this activation of the immune system potentially warrants combination treatment with PD-(L)1 blockade.
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MINI 30 - New Kinase Targets (ID 157)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:K. Park, M. Villalona
- Coordinates: 9/09/2015, 18:30 - 20:00, Four Seasons Ballroom F3+F4
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MINI30.06 - Activity of AUY922 in NSCLC Patients With EGFR Exon 20 Insertions (ID 1744)
18:30 - 20:00 | Author(s): E. Smit
- Abstract
- Presentation
Background:
EGFR exon 20 insertions (ins20) represent a rare subtype (4%) of EGFR mutations and are refractory to EGFR-specific tyrosine kinase inhibitors (TKIs). No effective targeted therapies exist for patients (pts) with ins20; median PFS on the irreversible EGFR TKI Afatinib is 2.8 months (mos). Based on a durable RECIST partial response (PR) to AUY922, a Heat Shock Protein 90 (Hsp90) inhibitor, observed in an EGFR ins20 patient in a previous study (NCT01124864), we designed a phase II investigator-initiated trial to assess the activity of AUY922 in NSCLC pts with EGFR ins20. Since pts with these mutations are rare, we identified other international investigators who have treated ins20 patients with AUY922. Here, we present the results of a pooled international experience of 21 patients with EGFR ins20 treated with AUY922 in the United States, Taiwan and the Netherlands.
Methods:
A total of 21 patients with EGFR in20 are included in this analysis. 14 were treated on a single-arm, multi-center, open-label study of AUY922 in advanced NSCLC pts with EGFR ins20 mutations in the US (NCT01854034). Five were treated on a multicenter Taiwanese trial of AUY922 across a variety of molecular NSCLC subtypes (NCT01922583) and two were treated on a compassionate-use basis in the Netherlands. The starting dose of AUY922 was 70mg/m2 IV weekly for all patients.
Results:
21 pts, including 14 females and 7 males, average age 55 (range, 27-75) were included in this analysis. The median number of prior therapies was 2 (range, 1-6.) 6 pts received a prior EGFR TKI; none responded to TKI monotherapy. The most common AUY922-related toxicities were grade 1-2 visual changes (18/21; 86%) diarrhea (18/21; 86%) and fatigue (15/21; 71%). The only treatment-related grade 3 toxicities was hypertension (2/21; 1%) and AST elevation (1/21; 0.5%). There was one death on study, related to pre-existing comorbidity/unrelated to AUY922. Among the 21 patients treated, 5 achieved a partial response by RECIST 1.1 (ORR 24%) (Figure 1.) The median PFS estimate is 3.9 mos (95% CI, 2.9 to 10.7.) 6 patients remain on treatment at the time of abstract submission. Updated results and correlation with specific ins20 mutations will be presented. Figure 1
Conclusion:
This international experience suggests that AUY922 may be an active therapy for advanced NSCLC pts with EGFR ins20 mutations with an ORR 24% and median PFS 3.9 mo. AUY922 is generally well-tolerated, though reversible low-grade ocular toxicity is common. Further study of AUY922 in this population is warranted.
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ORAL 28 - T Cell Therapy for Lung Cancer (ID 132)
- Event: WCLC 2015
- Type: Oral Session
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:P.S. Adusumilli, E. Smit
- Coordinates: 9/08/2015, 16:45 - 18:15, Four Seasons Ballroom F1+F2
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ORAL28.06 - Discussant for ORAL28.01, ORAL28.02, ORAL28.03, ORAL28.04, ORAL28.05 (ID 3463)
16:45 - 18:15 | Author(s): E. Smit
- Abstract
- Presentation
Abstract not provided
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ORAL 35 - Surgical Approaches in Localized Lung Cancer (ID 155)
- Event: WCLC 2015
- Type: Oral Session
- Track: Treatment of Localized Disease - NSCLC
- Presentations: 1
- Moderators:M. de Perrot, J. Mitchell
- Coordinates: 9/09/2015, 16:45 - 18:15, 601+603
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ORAL35.03 - Salvage Surgery for Local Failures after Stereotactic Ablative Radiotherapy for Lung Malignancies (ID 626)
16:45 - 18:15 | Author(s): E. Smit
- Abstract
- Presentation
Background:
Stereotactic ablative radiotherapy (SABR) is a guideline-recommended therapy for unfit patients with early stage non-small cell lung cancer (NSCLC), and for pulmonary metastases. Experience with SABR for potentially operable patients is also increasing, and salvage surgery may have a role in patients who subsequently develop a local tumor recurrence. However, prior high-dose SABR could theoretically increase local adhesions and compromise wound healing. As the published literature is limited, we describe our experience with salvage surgery in 17 patients who developed a local recurrence after SABR.
Methods:
Patients who underwent surgical salvage for a local recurrence following SABR for pulmonary malignancies were identified from two Dutch institutional databases, as well as cases provided by other Dutch surgeons. Complications were scored using the Dindo-Clavien-classification.
Results:
Seventeen patients who underwent surgery for a local recurrence were identified. Patients were treated with SABR for either primary non-small cell lung cancers (N=9) or solitary metastasis (N=8). Four patients with solitary metastasis underwent surgery twice each for separate recurrences. Median time to local recurrence was 15.6 months. Recurrences were diagnosed with CT- and/or [18]FDG-PET-imaging, with 5 patients also having a pre-surgical pathological diagnosis. Extensive adhesions were observed during 5 resections, requiring conversion from a thoracoscopic procedure to thoracotomy in 3 procedures. Four patients experienced complications post-surgery; grade 2 (N=2) and grade 3a (N=2), respectively. All resected specimens confirmed the presence of viable tumor cells. Median length of hospital stay was 7 days (range 4-15 days) and 30-day mortality was 0%. Lymph node dissection revealed mediastinal metastases in 3 patients, all of whom received adjuvant therapy. Median follow-up after surgery was 41 months and median overall survival was 38 months.
Conclusion:
Experience with 21 surgical procedures for local recurrences post-SABR revealed only two grade IIIa complications, and a 30-day mortality of 0%. Median overall survival after surgery was 38 months. These results suggest that salvage surgery may be safely performed in selected patients following SABR.
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ORAL 37 - Novel Targets (ID 146)
- Event: WCLC 2015
- Type: Oral Session
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:S.S. Ramalingam, E. Thunnissen
- Coordinates: 9/09/2015, 16:45 - 18:15, Mile High Ballroom 4a-4f
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ORAL37.05 - Prevalence and Clinical Association of MET Gene Amplification in Patients with NSCLC: Results from the ETOP Lungscape Project (ID 444)
16:45 - 18:15 | Author(s): E. Smit
- Abstract
Background:
The reported prevalence of MET gene amplification in non-small cell lung cancer (NSCLC) varies from 0-21% and clinical correlations are emerging slowly. In a well-defined NSCLC cohort of the ETOP Lungscape program, we explore the epidemiology, the natural history of MET amplification and its association with MET overexpression, overall survival (OS), relapse-free survival (RFS) and time to relapse (TTR).
Methods:
Resected stage I-III NSCLC, identified based on the quality of clinical data and FFPE tissue availability, were assessed for MET gene copy number (GCN) and expression analysis using silver in-situ hybridization (SISH) and immunohistochemistry (IHC), respectively, on TMAs (MET and centromere-specific probes; anti total c-MET antibody, clone SP44; Ventana immunostainer). MET amplification was defined as MET/centromere ratio ≥2 with average MET GCN ≥4, high MET GCN at two levels as ≥median CGN and ≥5 (irrespective of amplification) and MET IHC+ as 2+ or 3+ intensity in ≥50% of tumor cells. Sensitivity analysis to define the amplification’s thresholds was also performed. All cases were analysed at participating pathology laboratories using the same protocol, after successful completion of an external quality assurance (EQA) program.
Results:
Currently 2709 patients are included in the Lungscape iBiobank (median follow-up 4.8 years, 53.3% still alive). So far, 1547 (57%) have available results for MET GCN with amplification detected in 72 (4.7%; 95%CI: 3.6%, 5.7%) and high MET GCN (≥5) in 65 (4.2%; 95%CI: 3.2%, 5.2%). The median value of average MET GCN per cell is 2.3. IHC MET expression is available for 1515 (98%) of these cases, 350 (23%) of which are MET IHC positive [170 cases (49%) 3+, 180 (51%) 2+]. The median age, for the cohort of 1547 patients, is 66.2 years, with 32.8% women, and 13.5%, 29.7%, 54% never, current, former smokers, respectively. Stage distribution is: IA 23.6%, IB 24.6%, IIA 17%, IIB 12.1%, IIIA 20.9%, IIIB 1.8%, while 52.7%, are of adenocarcinoma and 40.0% of squamous histology. MET amplification and high MET GCN (≥5) are not significantly associated with any histological tumor characteristics or stage (multiplicity adjusted alpha: 0.005). High MET GCN (≥2.3) is less frequent in current smokers (38.3% vs. 55.6% for former or non-smokers, p<0.001). MET amplification and high MET GCN are significantly associated with IHC MET positivity (p<0.001 in all cases). MET amplification is present in 9.7% of IHC MET+ vs 3.1% of IHC MET- patients and high MET GCN (≥5) in 8.6% of IHC MET+ vs 2.8% of IHC MET- patients. MET amplification ranges from 0 to 16% between centers, while high MET GCN (≥5) and (≥2.3) from 0% to 12%, and 11.8% to 98.9%, respectively. MET amplification and both levels of high MET GCN are not associated with OS, RFS or TTR.
Conclusion:
The preliminary results for this large, predominantly European, multicenter cohort demonstrate that MET amplification assessed by SISH prevails in 4.7% of NSCLC, is associated with strong MET expression, and has no influence on prognosis. The large inter-laboratory variability in GCN despite EQA efforts may highlight a critical challenge of MET SISH analysis in routine practice.
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P3.01 - Poster Session/ Treatment of Advanced Diseases – NSCLC (ID 208)
- Event: WCLC 2015
- Type: Poster
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 2
- Moderators:
- Coordinates: 9/09/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P3.01-022 - A Prospective Multicenter Study for ALK IHC+ Metastasized NSCLC (ID 2566)
09:30 - 17:00 | Author(s): E. Smit
- Abstract
Background:
Pulmonary adenocarcinomas may harbor driver mutations, that sensitize tumors to drugs that specifically target the genetic alteration. Metastasized NSCLC with an EML4-ALK translocation are sensitive to a range of tyrosine kinase inhibitors, of which crizotinib is most extensively studied. ALK-positive NSCLC was determined in a phase III trial with fluorescence in situ hybridisation (ALK FISH+). ALK immunohistochemistry (IHC) seems to run parallel with ALK FISH positivity. However discrepant cases occur, which include ALK IHC+ FISH-. The aim of this study is to collect cases with ALK IHC+ and compare within this group response to crizotinib treatment of ALK FISH+ cases with ALK FISH- cases.
Methods:
A prospective multicenter investigator initiated research study was started in Europe. This study is supported by Pfizer. Cases diagnosed with ALK IHC+ lung cancer (5A4 or D5F3) treated with crizotinib are collected centrally. Slides are submitted centrally for validation of ALK IHC (with ETOP and Ventana protocol), ALK FISH (with Vysis probes) and DNA analysis.
Results:
The study started on April 1 2014 and is still open. Currently 10 centers are actively participating. 1443 cases have been examined with ALK IHC of which 39 (2.7%) recorded positive. 24 cases have been submitted to the database. The validation process is still ongoing. The fraction of ALK IHC+ FISH- cases is low. Two cases with ALK IHC+ FISH- metastastatic NSCLC responded to crizotinib treatment. In two cases ALK positivity could not be confirmed (ALK IHC- and ALK FISH-). These patients had progressive disease following crizotinib treatment.
Conclusion:
A clinically relevant question what the effect of ALK inhibitor treatment is on metastatic NSCLC ALK IHC+ FISH- compared to ALK IHC+ FISH+ is examined. Other centers with interested collaborating physicians are invited to participate.
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P3.01-044 - FDG-PET/CT Based Response Prediction of Stage IV NSCLC Treated with Paclitaxel-Carboplatin-Bevacizumab with or without Nitroglycerin (ID 1229)
09:30 - 17:00 | Author(s): E. Smit
- Abstract
Background:
A prospective study in stage IV non-small cell lung cancer (NSCLC) patients was performed to assess the predictive value of early response of the primary tumor evaluated by [18F]FDG-PET/CT to bevacizumab containing combination therapy with or without nitroglycerin (NTG) patches as first line treatment. NTG is a vasodilator which is hypothesized to increase tumor blood flow thereby decrease hypoxia, and 1) leading to a decrease in [18F]FDG uptake, and 2) facilitating early response assessment using [18F]FDG to predict treatment outcome.
Methods:
In total, 223 patients were randomized between carboplatin-paclitaxel-bevacizumab (PCB) with or without NTG (day -2 to +3; NVALT12 trial, NCT01171170). 78 patients were available for image analysis having undergone an [18F]FDG-PET/CT scan prior to the first cycle of chemotherapy and a second (optional) [18F]FDG-PET/CT scan at day 1-2 after start of the second cycle. The primary gross tumor volume (GTV) was delineated on both PET/CT scans. On the [18F]FDG-PET scan, the maximum standardized uptake value (SUV), mean SUV, peak SUV and total lesion glycolysis (TLG defined as SUVmean*CTvolume) were calculated and correlated with progression-free survival (PFS) and overall survival (OS). Early response assessment was quantified using relative changes in [18F]FDG-PET uptake parameters of the GTV expressed as delta. The median of the parameter of interest was used as cut-off value for both study arms for analysis using cox regression. Furthermore response was assessed according to PERCIST and RECIST.
Results:Hazard ratio os SUV parameters > versus < the median for PFS and OS
1) On average no decrease in [18F]FDG-PET uptake was observed for the experimental NTG group. However, patients in the experimental group showed a significantly larger variation in most SUV parameters of the second PET/CT scan compared to control group without NTG. 2) In table 1 the hazard ratios are shown for the relative delta SUVmax, SUVmean, SUVpeak and TLG for both study arms. In the experimental group, patients with a small delta TLG (<64%) had a shorter PFS than patients with a larger change in TLG (HR:1.064; 95% CI 1.002-1.131; p=0.043). Response assessed by PERCIST and RECIST did not predict for a longer PFS or OS.SUV parameter median PFS OS HR (p-value) 95% CI HR (p-value) 95% CI Delta PCB+NTG (%) SUVmax 40.4 1.026 (0.408) 0.966-1.090 1.006 (0.844) 0.945-1.071 SUVmean 39.9 1.048 (0.127) 0.987-1.113 1.034 (0.279) 0.973-1.099 SUVpeak 42.3 1.035 (0.258) 0.975-1.100 1.016 (0.615) 0.955-1.082 TLG 64.5 1.064 (0.043) 1.002-1.131 1.039 (0.221) 0.977-1.106 Delta PCB (%) SUVmax 53.2 1.027 (0.454) 0.957-1.103 1.009 (0.810) 0.939-1.084 SUVmean 51.6 1.027 (0.465) 0.957-1.102 1.011 (0.766) 0.941-1.086 SUVpeak 53.9 1.040 (0.281) 0.969-1.116 1.018 (0.623) 0.947-1.094 TLG 75.9 0.994 (0.873) 0.927-1.066 0.998 (0.951) 0.928-1.072
Conclusion:
Adding NTG did not result in a decrease in [18F]FDG-PET uptake compared to patients without NTG although NTG increased variability of the measured SUV parameters. Patients in the experimental NTG arm without an early response on [18F]FDG-PET/CT imaging had a worse PFS than patients with a response. For the group without NTG no difference was observed. Also, RECIST and PERCIST were not predictive.
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P3.04 - Poster Session/ Biology, Pathology, and Molecular Testing (ID 235)
- Event: WCLC 2015
- Type: Poster
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 2
- Moderators:
- Coordinates: 9/09/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P3.04-040 - Comparison of Histology with Genome-Wide Copy Number Profiling in Patients with Metachronous or Synchronous Tumors (ID 3035)
09:30 - 17:00 | Author(s): E. Smit
- Abstract
Background:
Multiple synchronous and metachronous lung tumors are frequently encountered in patients with lung cancer. In addition, tumors of head and neck (usually squamous cell carcinoma) have a chance for a second primary malignancy in the lung. For treatment purposes it is important to know whether tumors are related (clonal = metastases) or not (multiple primaries). Histopathological comparison of the synchronous or metachronous tumors has been associated with molecular analysis. The purpose of this study is to examine the value of histopathological scoring with genome-wide copy number profiling for determination of clonality.
Methods:
From cases in which array CGH for clonality analysis performed between 2006 and 2012 were selected if at least one intrathoracic tumor was present. In the first years genome-wide copy number profiling was performed with arrayCGH and later with shallow sequencing. Results of the genome-wide copy number profiling were compared to histological (sub)typing.
Results:
100 tumor pairs from 59 patients were examined. 32 pairs were discovered simultaneously (synchronous), the other 68 were metachronous. The histopathological diagnosis was similar in 74 cases (74%). genome-wide copy number profiling revealed evidence for clonality in 55% of the pairs, no-clonality in 28% and was undetermined in 17%. Comparing of histology with genome-wide copy number profiling revealed concordancy in 54 pairs ( 74%; 44 clonal en 10 non-clonal). In 18 of the 62 pairs where histology was similar the genome-wide copy number profiling revealed a non-clonal pattern. In 11 out of 21 pairs where histology differed between the pairs, genome-wide copy number profiling revealed a clonal pattern. Thus histology was not prognostic in 29/83 pairs (35%).
Conclusion:
For the determination of clonality in lung cancer histological examination is discordant with genome-wide copy number profiling in 35% of the comparisons. As histology is a poor predictor of clonality, genome-wide copy number profiling is preferred for clonality analysis between tumors.
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P3.04-053 - SPECTAlung: Screening Patients with Thoracic Tumors for Efficient Clinical Trial Access (ID 1386)
09:30 - 17:00 | Author(s): E. Smit
- Abstract
Background:
The identification of molecular alteration and its targeting has completely changed the treatment and prognosis of lung cancer. However, designing and implementing clinical trials in small subsets of patients with a particular molecular alteration is challenging because of lack of uniform screening program. Across Europe, screening for molecular alterations is center or country dependent and, generally limited to a small subset of genes. SPECTAlung is the first European standardized, quality-assured molecular screening program of the European Organization for the Research and Treatment of Cancer (EORTC) in collaboration with the European Thoracic Oncology Platform (ETOP) to facilitate clinical trial access for patients with thoracic tumors. It is expected to test 500 to 1000 patients each year with the overall goal of offering patients clinical trials with targeted agents.
Methods:
Patients sign the informed consent for their tumor tissue to be collected, centralized and processed according to defined international quality control standards at Gustave Roussy Biobank (Villejuif, France). Next Generation Sequencing (NGS) is performed at Sanger Institute (Cambridge, UK) where a panel of about 360 genes is analyzed for mutation, rearrangements and gene copy number. Eligible patients will be those having a pathological diagnosis of any thoracic tumor (lung cancer, malignant pleural mesothelioma and thymic malignancies) at any stage of disease, availability of tumor tissue, age at least 18 years, PS 0-2, life expectancy > 3 months, no active malignancy in the 5 years before study entry and absence of any exclusion criteria that may prevent inclusion into clinical trials. A molecular report will be released to the investigator highlighting identified molecular alterations and also the trials for which the patients might be eligible. The study has been submitted to ethical committees of 15 selected highly specialized and qualified thoracic centres in 12 countries in Europe. EORTC and ETOP will promote the implementation of clinical trials in molecularly selected groups of patients at the SPECTAlung centers. SPECTAlung offers innovative and attractive models of collaboration with commercial and research organizations, by improving patient access to novel therapeutic clinical trial and support the development of personalized medicine. Clinical trial registry number NCT02214134.
Results:
Not applicable
Conclusion:
Not applicable
